Positron Emission Tomography Imaging in Brain Injured Patients Paul Vespa, MD Professor Director of Neurocritical Care UCLA Brain Injury Research Center
Positron Emission Tomography Imaging in Brain
Injured Patients
Paul Vespa, MD Professor
Director of Neurocritical Care UCLA Brain Injury Research Center
Outline
• Clinical Context of imaging • Practical issues • Major Hypotheses/Questions being
addressed – Ischemia – Metabolic crisis – Chronic traumatic encephalopathy – Prognosis
ICU Environment
Human PET Center
Limitations to human experimentation
• Timing of studies is dependent on patient stability
• Radiation dosing is limited • Missing data points require special
statistics
Basic Design • Structural imaging with CT and MRI • PET image with an available clinical PET
ligand – Dynamic quantitative image for regional
assessment – FDG – O2 – F18- MISO – FDDNP – C-PIB
TBI results in metabolic disturbance
• Cascade of metabolic events after TBI
• Initial depolarization event most important
Katayama et al 1990
Disturbed metabolism after TBI
• Reduced CBF related to decreased demand, impaired microcirculation (low NO), and iatrogenic causes (HV, CPP)
• Decreased rate of CMRO2 related to mitochondrial dysfunction
• Increase glucose utilization CBF
FDG
Time course of TBI • Early hypotension and brain ischemia
within the initial 12 hours • Mass effect that requires surgery • ICP related to brain edema • Periodic insults due to seizures
– Possibly brain ischemia events • 7-10 days of disturbed brain
hemodynamics and altered brain metabolism in the ICU
Classical Ischemia
Increased OEF =0.79
Reduced CBF = 20
Reduced CMRO2 =1.2
Classical Ischemia
Oxidative metabolism is reduced to a critical threshold
• Menon et al 2004 • Large regions of the brain have critically low
rates of CMRO2 • Regions of not directly adjacent to contusions
Coles, Menon et al J Cereb Blood Flow Metab 2004
Hyperventilation not inducing ischemia – Diringer et al 2005
Absence of brain ischemia adjacent to a contusion OEF = 0.25
CBF = 49.6 cc/100gm/min
Asymmetric OEF with right side higher
PET O15 OEF = .50 in red crescent
Goals of treatment
• The goal is to maintain adequate perfusion with cerebral blood flow that is sufficient to supply the increased energy demand
• PET can provide evidence of response in CBF to changes in blood pressure or supplemental fluids or blood
•6 patients with SAH vasospasm •O-15 SBF PET before and after fluid challenge • 1 L Normal Saline fluid challenge
Jost, Diringer et al 2005
J Neurosurgery, 116, March 2012
Reversing ischemia through hyperoxia
• Increase in CMRO2 in tissue at risk by delivery of normobaric hyperoxia (but not for whole brain)
• Reduction in LPR 34.1 to 32.5 (P < 0.035)
Nortje, Menon et al 2008
PET and Microdialysis after SAH Sarrafzadeh and Unterberg , 2004
PET with SAH cerebral Ischemia using F18-MISO
Saffarzadeh, Unterberg et al 2010
F18- MISO in SAH
Non-ischemic Metabolic Crisis
N = 28 TBI Hyperglycolysis in 12/28 Early after TBI day < 5
Hyperglycolysis after TBI
Regional Hyperglycolysis
Seizures associated with hyperglycolysis
CMRglc 2.9-3.2
CBF 21-24
CBF 16
Microdialysis: Glucose 2.0 Lactate 0.8 Glutamate 1.6 Glycerol 44 L/P 56
CBF 37
PET in TBI showing regional metabolic crisis and low CBF
Elevated LPR without ischemia LPR = 100 during PET
LPR ratio
020406080
100120140160
59 60 61 62 63 64 65
PIH
Lact
ate/
pyru
vate
Vespa et al J Cereb Blood Flow Metab 2005
0102030405060708090
100
11 13 15 17 19 21 23 25 27 29 31 33
ICPSJVO2CPP
PI hour
Post TBI seizures lead to additional disturbance of metabolism without ischemia
EEG
CT
ICP, SJVO2 and CPP
Vespa et al Neurology 2010
Brin(green)Glycerol
0
10
20
30
40
50
75 85 95 105 115 125 135 145 155
Post-Injury Hrs
ICP
0.00
5.00
10.00
15.00
20.00
72 82 92 102 112 122 132 142 152 162
PIH
mm
Hg
SjvO2
0.00
20.00
40.00
60.00
80.00
100.00
72 82 92 102 112 122 132 142 152 162
PIH
% s
at
seizures
Increased glycolysis
Initial CT Post-op
MD glycerol increased
Post-traumatic seizures elicit increased glycolysis
Use of PET to determine optimal glucose delivery
Glucose = 77 Glucose = 127
Vespa et al Crit Care Medicine (in press for 2012)
Increase in hyperglycolysis under conditions of tight glycemic control
• Regional variation of baseline glucose metabolism
• Increased glucose metabolism when serum glucose is restricted
• Similar changes in white and grey matter • Least change in pericontusional tissue • MD glucose decreased and glycerol higher
under tight glycemic control
Vespa et al Crit Care Med 2012
Progressive Disease and Prognosis
• TBI and other acute neurocritical care illnesses are disease processes, not just acute injuries
• PET can be used to study the prognosis of the chronic disease and to investigate possible disease mechanisms – Programmed cell death – Tau and Amyloid deposition
Chronic Atrophy at 6 months
Primary acute injury is hemorrhagic, not ischemic
Metabolic Rates acutely after TBI
Chronic atrophy
CMRO2
CBF
CMRglucose Frontal lobe
Frontal Temporal Parietal
Long term atrophy
Acute Chronic at 6 months
Brain Atrophy after NCSE in TBI
Hippocampal atrophy after post-traumatic seizures
Acute FLAIR MRISubdural Hemorrhage
Acute ADC MRIHippocampus = 1001 u2/s
Chronic MRIHippocampal Atrophy
Status Epilepticuson post injury day 5
Increased hippocampal atrophy in patients with post-traumatic seizures
Vespa et al Neurology 2010
Impaired long term cognition and cortical atrophy after metabolic crisis
Wright et al 2013 Dinov et al (in press)
FDG in Mild TBI – relation to memory disorder
Z scores showing differences in FDG in various regions
Chronic tau deposition in long term CTE in NFL players - Small et al 2013
FDDNP in NFL Small et al 2013
N = 12 military blast injury N = 12 blunt TBI Resting state FDG PET - semi quantitative Comparison of ROI vs Normals
Summary of imaging in acute brain injury